Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma
Feasibility of Targeting Traf2-and-Nck-Interacting Kinase in Synovial Sarcoma
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DOI：
10.3390/cancers12051258
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发表时间：
2020-05-01
期刊：
影响因子：
5.2
通讯作者：
Masuda, Mari
中科院分区：
文献类型：
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作者：
Sekita, Tetsuya;Yamada, Tesshi;Masuda, Mari
背景资料：转移性滑膜肉瘤患者的治疗仍然具有挑战性，并且需要开发新的分子疗法。Wnt信号转导失调与滑膜肉瘤有关。Traf 2和Nck相互作用激酶（TNIK）是Wnt靶基因的重要转录共调节因子。我们研究了TNIK的小干扰RNA（siRNA）和小分子TNIK抑制剂NCB-0846对滑膜肉瘤的疗效。方法：检测TNIK在20例滑膜肉瘤中的表达。在四种滑膜肉瘤细胞系和小鼠异种移植模型中评价了NCB-0846的疗效。结果如下：我们发现，滑膜肉瘤细胞系与Wnt激活高度依赖于TNIK的表达增殖和生存。NCB-0846通过阻断Wnt靶基因（包括MYC）诱导滑膜肉瘤细胞凋亡，经口给药NCB-846诱导通过接种滑膜肉瘤细胞建立的异种移植物消退。讨论内容：很明显，Wnt信号传导的激活是滑膜肉瘤发病机制中的原因，但尚未批准靶向该途径的分子治疗。这项研究首次揭示了TNIK抑制剂在滑膜肉瘤中的治疗潜力。
Background: The treatment of patients with metastatic synovial sarcoma is still challenging, and the development of new molecular therapeutics is desirable. Dysregulation of Wnt signaling has been implicated in synovial sarcoma. Traf2-and-Nck-interacting kinase (TNIK) is an essential transcriptional co-regulator of Wnt target genes. We examined the efficacy of a small interfering RNA (siRNA) to TNIK and a small-molecule TNIK inhibitor, NCB-0846, for synovial sarcoma. Methods: The expression of TNIK was determined in 20 clinical samples of synovial sarcoma. The efficacy of NCB-0846 was evaluated in four synovial sarcoma cell lines and a mouse xenograft model. Results: We found that synovial sarcoma cell lines with Wnt activation were highly dependent upon the expression of TNIK for proliferation and survival. NCB-0846 induced apoptotic cell death in synovial sarcoma cells through blocking of Wnt target genes including MYC, and oral administration of NCB-846 induced regression of xenografts established by inoculation of synovial sarcoma cells. Discussion: It has become evident that activation of Wnt signaling is causatively involved in the pathogenesis of synovial sarcoma, but no molecular therapeutics targeting the pathway have been approved. This study revealed for the first time the therapeutic potential of TNIK inhibition in synovial sarcoma.